DE3209429A1 - AGENT FOR IMPROVING THE RESORPTION OF INJECTED ANTIBACTERIAL EFFECTIVE SUBSTANCES AND COMBINATIONS CONTAINING A BENZYAMINE DERIVATIVE - Google Patents

Description

BOEHRINGER INGELHEIM Case 3/227

VETMEDICA GMBH 'Dr.Fl / fra / Kp

D-6507 Ingelheim

Means to improve the absorption of injected antibacterial substances and combinations, containing a benzylamine derivative

It is known from the literature that benzylamine derivatives are used in human and veterinary medicine as bronchosecretolytic agents will. The best-known representatives of these benzylamine derivatives are N- (2-amino-3,5-dibromobenzyl) -N-methyl-cyclohexylamine hydrochloride (Generic name: Bromhexine) and N- (2-Amino-3,5-dibromo-benzyl) -trans-4-hydroxy-cyclohexylamine hydrochloride (Generic name: Ambroxol). These compounds significantly increase the amount of secretion, in addition, there is a decrease the viscosity of the secretion, a reduction in the concentration of solids in the respiratory tract fluid and its specific gravity observed, which characterizes the benzylamine derivatives as secretolytics.

It is also known from the literature that the above-mentioned when administered orally Benzylamine derivatives together with an antibiotic, in particular with oxytetracycline and erythromycin, with a sulfonamide, like sulfadiazine, the infiltration of these substances into the bronchial secretion is increased. The same also applies to the body's own immunoglobulins that are not administered separately. These However, an increase in the concentration of bronchial secretions is not a consequence of the benzylamine concentrations mentioned above.

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vate-induced increased absorption from the intestine or a possibly delayed excretion via the kidneys, as both after No increase in blood levels could be observed after oral or intravenous administration.

Surprisingly, it has now been found that with parenteral Administration of a benzylamine derivative of the general formula

^ - ^R 2

, (D

Br ^? \> 2 - - _R

Ri

Br

and its physiologically compatible acid addition salts with inorganic or organic acids, the resorption of a parenteral Administered to the tissue alone, not optimally absorbable antibacterial substance or combination accelerated will. According to the invention, the higher blood levels with the same dosage make the antibacterial effective substance or combination achieves better and safer therapeutic success or it can - will no value placed on higher blood levels - their application rate compared to the amount required when administered alone Quantity can be reduced, that is, a not insignificant saving is achieved. In addition, the problem of residues is defused, because with the antibacterial substances and combinations in question, the injection site usually has the Tissue is the one that contains measurable residues of these substances for the longest.

In the general formula above, means

Usually a hydroxyl group in the 2- or 4-position or in the 2-position an amino group,

R ₂ ³ ii. Hydrogen atom or an alkyl group having 1 to 3 carbon atoms and

R _{3 is} a cyclohexyl group which is optionally substituted by a hydroxyl group.

The present invention thus relates to the new use of the benzylamine derivatives of the general formula I and their physiologically acceptable acid addition salts, preferably in veterinary medicine, to increase the resorption of less readily resorbable substances administered parenterally into the tissue antibacterially active substances or combinations, preferably with their simultaneous parenteral administration.

Preferred benzylamine derivatives of the above general formula I, however, are those in which R- and R- together with the intermediate Nitrogen atom the N-methyl-cyclohexylamino-, N-Xthyl-cyclohexylamino-, trans-4-hydroxy-cyclohexylamino- or represent cis ~ 3-hydroxy-cyclohexylamino group.

A particularly preferred benzylamine derivative of the general above However, formula I provides the compound N- (3,5-dibromo-2-hydroxy-benzyl) -trans-4-hydroxy-cyclohexylamine and its physiologically compatible acid addition salts with inorganic or organic acids, in particular its hydrochloride.

According to the invention, for example, antibacterial substances are used the following into consideration:

a tetracycline group antibiotic, e.g. B. Oxytetracycline, Oxytetracycline hydrochloride, rolitetracycline or doxycycline,

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a sparingly soluble antibiotic of the β-lactam group, e.g. B. Procaine penicillin, benethamine penicillin, benzathine penicillin, the benzathine salts of oxacillin, cloxacillin, ampicillin and the cephalosporins, erythromycin and its derivatives such as 9-deoxy-11-deoxy-9,1 1-, £ imino- / 2 ~ (2-methoxyethoxy) äthyliden7oxy7- (9F) -erythromycin, Spiramycin, tylosin, oleandomycins Chloramphenicol or

a sulfonamide, e.g. B. sulfadiazine, sulfadoxine, sulfamethoxazole, Sulfadimethoxine, sulfadimldine or sulfathiazole, or a sulfonamide combination with an agonist such as trimethoprim, e.g. the suIfadimidine-sulfathiazole-trimethoprim cortibination,

and, if applicable, their corresponding forms of deposit.

The present invention also relates to the new combinations which can be administered parenterally into the tissue and which contain a benzylamine derivative of the above general formula I and an antibacterially active one which alone is not optimally absorbable Substance or combination in addition to one or more customary inert diluents or carriers, preferably their application forms suitable for intramuscular administration.

Preferred combinations here are those which have a benzylamine derivative of the above general formula I, in which R. is a hydroxy group and R ₂ and R_ together with the nitrogen atom in between have the meanings mentioned above, but expediently the N-ethyl-cyclohexylamino-, trans-4 -Hydroxycyclohexylamino or cis-3-hydroxy-cyclohexylamino group, but preferably R-. in the 2-position represents the hydroxyl group and R ₁ and R 3 together with the nitrogen atom in between represent the trans-4-hydroxycyclohexyl group, and contain one of the above-mentioned antibacterial substances or combinations, or a combination consisting of

N- (2-amino-3,5-dibromo-benzy1) -N-methy1-cyclohexylamine and its physiologically compatible acid addition salts and an oxytetracycline long-term preparation, oxytetracycline hydrochloride long-term preparation, Rolitetracycline, doxycycline,

egg. ^ m «less soluble antibiotic of the ß-lactam group, z. B. Procciin penicillin, benethamine penicillin, benzathine penicillin, a benzathine salt made from oxacillin, cloxacillin, ampicillin and the cephalosporins,

Erythromycin or one of its derivatives such as 9-deoxy-11-deoxy-9,1 l-ß.mLno-ß- (2-methoxyethoxy) -äthylidej ^ oxyy- (9F) -erythromycin, spiramycin, tylosin, oleandomycin or

a sulfonamide such as sulfadiazine, sulfadoxine, sulfamethoxazole, Sulfadimethoxine, sulfadimidine or sulfathiazole or a sulfonamide combination with an agonist such as trimethoprim, e.g. the sulfadimidine-sulfathiazole-trimethoprim combination, or a combination consisting of

N- {2-Amino-3,5-dibromo-benzyl) -trans-4-hydroxy-cyclohexylamine and its physiologically acceptable acid addition salts and an antibiotic of the tetracycline group, e.g. B. Oxytetracycline, Oxytetracycline hydrochloride, rolitetracycline or doxycycline,

a poorly soluble antibiotic of the ß-lactam group, e.g. procaine penicillin, benethamine penicillin, benzathine penicillin, a benzathine salt of oxacillin, cloxacillin, ampicillin and the cephalosporins,

Erythromycin or one of its derivatives, such as, for example, 9-deoxy-11-deoxy-9.11 - £ Ümino [2- (2-methoxyethoxy) -äthylidenjoxyj- (9F) -erythromycin, spiramycin, tylosin, oleandomycin, chloramphenicol or one

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Sulfonamide, e.g. sulfadiazine sulfadoxin, sulfamethoxazole, suI-fadimethoxin, Sulfadimidine or sulfathiazoles or a sulfonamide combination with an agonist such as trimethoprim, e.g. the sulfadimidine-sulfathiazole-trimethoprim combination, as well if applicable, their corresponding forms of deposit.

However, the following are particularly preferred combinations:

Combinations of N- (2-amino-3,5-dibroni-benzyl) -N-methyl-cyclohexylamine and its physiologically compatible acid addition salts or N- (3,5-dibromo-2-hydroxy-benzyl) -trans-4-hydroxycyclohexylamine as well as its physiologically compatible acid addition salts with erythromycin / 9-deoxy-11-deoxy-9,11- ^ imino- / 2- (2-methoxyethoxy) -äthylide_n7oxvy- (9F) -erythromycin, spiramycin, Tylosin, oleandomycin, benzyl penicillin, ampicillin, oxacillin, cloxacillin, rolitetracycline, doxycyciin and theirs Salts, as well as a sulfonamide and its salts, also in combination with trimethoprim,

and combinations of N- (3,5 ~ dibromo-2-hydroxy-benzyl) -trans-4-hydroxy-cyclohexylamine and its physiologically acceptable acid addition salts with oxytetracycline and its salts and Chloramphenicol.

For example, the absorption-promoting effect of benzyl aminderiva te

A = N- (2-amino-3, S-dibromo-benzyD-N-methyl-cyclohexylamine-hydro-

B = N- (2-amino-3,5-dibromobenzyl) -trans-4-hydroxy-cyclohexylamine hydrochloride and

C = N- (3,5-dibromo-2-hydroxy-benzyl) -trans-4-hydroxy-cyclohexylamine hydrochloride

checked as follows:

Cattle, pigs and sheep - each the same 10 animals per group - were given only the antibacterial in question once Substance or combination, once with the combination of the benzyl ^ uninderivates with the same antibacterial substance or K. ^ nbination treated intramuscularly. Both treatments are carried out i. An interval of 8 days to ensure the total excretion of the substance (s) administered during the first dose. The order of the treatments was variable, i.e. in some cases the antibacterial substance or combination was used first (Control), in some cases the combination with the benzylamine derivative administered (Experimental group). In some cases the trials were carried out in a "cross-over" arrangement, i.e. at the first appointment 5 animals received the antibacterial substance or combination, 5 animals the combination with the benzylamine derivative. When repeating 8 days later, the treatment of the animals was reversed.

Blood samples were taken every 1 or 2 hours during the day and after 24 hours, and in some cases after 32 hours Hours, in 2 cases (long-term preparation) also after 48 and 72 hours. The determination of the antibiotic or sulfonamide levels of the blood serum was carried out according to generally accepted microbiological methods with test germs specific for each substance. Compared In each case, the areas under the blood level curves obtained were used as the total measure of the antibacterial activity. this resulted in the following for the combination of the benzylamine derivatives with the antibacterial substance or combination in question Increases in blood levels compared to the respective control group:

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Antibacterial
effective. Noun /
combination

Dose mg / kg Kgw

Benzylamine species
derivative

Dose mg / kg

% Increase in blood level compared to controls

Erythromycin

10 0.3 IM A cattle 10 0.6 IM C beef

10 0.6 IM A pig 10 1.2 IM A pig

16.1 21.4

59.1 31.4

Erythromycin 10
Derivative 10

1,2 in the A pig
1.2 in the C pig

15.3 45.4

Oxytetracycline hydrochloride

0.6 IM C beef

16.3

Oxytetracycline
Depot preparation

20 0.6 IM A pig 20 1.2 IM C pig

109.5 80.0

Tylosin 15th 0.3 in the. A. Beef 33.0 15th 0.6 in the. C. Beef 23.5 10 0.6 in the. A. pig 19.3 10 1.2 in the. A. pig 30.3 10 0.6 in the. C. pig 30.5 10 1.2 in the. C. pig 26.1 Sulfadimidine 24 0.6 in the. A. pig 29.6 Sulfathiazole 24 1.2 in the. A. pig 25.1 Trimethoprim 24 0.6 in the. C. pig 29.9 combination 24 1.2 in the. C. pig 20.3

1) blood levels monitored over 72 h; after 48 h 0.13 ^ ag / ml for Control, but 0.35 µg / ml for experimental group; after 72 h Control 0.00 jig / ml, test group still 0.19 pg / ml

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The benzylamine derivatives of the general formula I used according to the invention and their physiologically tolerable acid addition salts with inorganic or organic acids are well tolerated. For example, the acute toxicity (LD ₅₀ ) is at

Substance A> 400 mg / kg i.p., Substance B 268 mg / kg i.p. and Substance C> 8OO mg / kg i.p ..

On the basis of the biological data mentioned above, the benzylamine derivatives of the general formula I and their physiologically suitable Compatible acid addition salts, as already mentioned at the outset, to improve absorption from parenteral into tissue applied antibacterial substances or combinations and thus to improve and secure the therapeutic Success. The dosage is expediently above 0.1 mg / kg, but preferably between 0.2 and 2.0 mg / kg, and is limited in solutions by the solubility of the benzylamine derivative used. For example in water depending on the pH in the acidic range the maximum solubility of the

Substance A 0.2-5.0 mg / cm, substance B 16.6 mg / cm and substance C 0.1-1.0 mg / cm.

In oily vehicles, depending on the oil solubility of the benzylamine derivative Of course, higher concentrations can also be achieved, as well if the benzylamine derivative in suitable Vehicles in which it is not or not sufficiently soluble, is suspended.

In addition, the benzylamine derivative is expediently applied simultaneously with a therapeutic dose of the antibacterially active substance or combination to be applied.

For example, the single dose of oxytetracycline is 5-30 mg / kg, oxytetracycline hydrochloride 2-25 mg / kg, and blood tetracycline 15-50 mg / kg, doxycycline 2-5 mg / kg, erythromycin 5-20 mg / kg, 9-deoxy-11-deoxy-9,11- £ emino / 2- (2-methoxyethoxy) ethylidene / oxY7- ( 9F) -erythromycin 5-20 mg / kg, spiramycin 10-50 mg / kg, tylosin 5-20 mg / kg, chloramphenicol 10 50 mg / kg, sulfadiazine 15-50 mg / kg, sulfadiazine-sulfathiazole-trimethoprim 15-30 mg / kg, sulfadoxine trimethoprim 15-30 mg / kg, procaine penicillin 2,000-20,000 IU / kg, benzathine penicillin 6,000-25,000 IU / kg, ampicillin 2-15 mg / kg, oxacillin 5-15 mg / kg or cloxacillin 5-15 mg / kg.

Suitable dosage forms are, for example, the following:

Injection preparations, aqueous, water-miscible or oily in nature, in which the antibacterial substances in question are dissolved or suspended in a concentration suitable for practice. The same applies to the benzylamine derivatives, depending on their solubility or their salts, one substance also being dissolved and the other being in suspension in the same preparation can. In cases where an aqueous solution is desired, for reasons of insufficient stability, e.g. B. the antibiotic, but is not appropriate, the combination ready for injection is only shortly before application by dissolving or suspending Dry substance produced in the solvent containing the benzylamine derivative.

The benzylamine derivatives used according to the invention of the general Formula I and their physiologically acceptable acid addition salts are known in the literature (see U.S. Patents 3,336,308, 3,536,713, and 4,113,777).

The following examples are intended to explain the invention in more detail:

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example 1

Two-compartment preparation with 9-deoxy-11-deoxy-9.11 - / JmLno- / 2- (2-methoxyethoxy) ethylidene, oxyy- (9F) -erythromycin-lactobionate and N- (2-amino-3,5 -dibromobenzyl) -N-methyl-cyclohexylamine-hydro SLASü. '^ d (aqueous solution)

composition
a) Dry ampoule

Antibiotic 715.0 mg b) Solvent ampoule Active substance 75.0 mg Tartaric acid 37.5 mg Glycerine polyethylene glycoloxys tearat 250.0 mg glucose 200.0 mg

Aqua pro injectione ad 5.0 ml production

To produce the dry ampoule, the active ingredient is dissolved in water for injection purposes, through a suitable filter system, if necessary with the use of pyrogen adsorption layers, made sterile and pyrogen-free and under aseptic conditions filled in the desired doses into cleaned and sterilized 10 ml injection vials. Freeze drying this Vial is done in the usual way.

To produce the solution ampoules, the active ingredient and the excipients are successively dissolved in water for injection purposes, filtered in a manner analogous to the dry ampoule solution and filled into 5 ml ampoules. For sterilization, sealed ampoules or sealed with rubber stoppers and AIuminiumbördelkappen vials are heated for 20 minutes 121 ⁰ C.

Example 2

Two-compartment preparation with 9-deoxy-11-deoxy-9,1 1- £ iinino- / 2- (2-methoxyethoxy) -äthylldej} / oxy _ / - (9F) -erythromycin-lactobionate and N- (2-amino- 3,5-dibromobenzyl) -N-methyl-cyclohexylamine-hydrochloride (aqueous solution)

composition

a) Dry ampoule

Antibiotic 3 575.0 mg

b) Solvent ampoule

Active ingredient 375.0 mg

Tartaric acid 187.5 mg glycerine polyethylene

glycol oxystearate 1,250.0 mg

Glucose 1,000.0 mg

Aqua pro injectione ad 2 5.0 ml

analogous to example 1

However, it is filled in 25 ml or 30 ml injections vial.

Example 3

oily suspension containing 9-deoxy-11-deoxy ~ 9,11- / imino- / 2- (2-methoxyethoxy) -äthyliden7ox ^; 7- (9F) -erythromycin and N- (3,5- dibromo-2- hydroxy-benzyl) -trans-4-cyclohexylamine hydrochloride

composition

Antibiotic 500.0 mg

Active ingredient 100.0 mg

- jar-

Benzyl alcohol 50.0 mg neutral oil to 5.0 ml

L antibiotic and the active ingredient are in a mixture of in the case of excipients, dissolved or suspended with heating and filled into cleaned and sterilized 5 ml ampoules under aseptic conditions.

Example 4

oily suspension containing 9-deoxy-11-deoxy-9,11- (2-methoxyethoxy) -ethylidene / oxyy- (9F) -erythromycin and N- (3,5- dibromo-2-hydroxy-benzyl) -trans- 4-cyclohexylamine hydrochlorld

composition

Antibiotic 2,500.0 mg

Active ingredient 500.0 mg

Benzyl alcohol 250.0 mg

Neutral oil ad 25.0 ml

Manufacturing

The antibiotic and the active substance are dissolved or suspended in a mixture of the two auxiliaries with heating filled into cleaned and sterilized 25 ml injection vials under aseptic conditions.

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Example 5

Two-compartment preparation with 9 ~ deoxy-11-deoxy-9,11- £ imino / 2- (2-methoxyethoxy) ethylidene / oxy? - (9F) -erythromycin lactobionate and N- (3,5-dibromo-2 -hydroxy-benzyl) -trans-4-hydroxy-cyclohexylamine hydrochloride (aqueous suspension)

715 , 0 mg 100 .0 mg 1 , 0 mg 250 , 0 mg 15th , 0 mg 5 , 0 ml

a) Dry ampoule

Antibiotic

b) suspension solution ampoule

Active substance

Polyethylene glycol stearate

Sorbitol

Methyl hydroxyethyl

cellulose

Aqua pro injectione ad

Manufacturing

To produce the dry ampoule, the active ingredient is dissolved in water for injection purposes, through a suitable filter system, possibly with the use of pyrogen adsorption layers, made sterile and pyrogen-free and under aseptic conditions filled in the desired doses into cleaned and sterilized 10 ml injection vials. Freeze drying this Vial is done in the usual way.

To produce the suspension solution ampoules, the Excipients dissolved in water for injections and the solution sterile and, if necessary, filtered pyrogen-free. The active ingredient is suspended in this solution under aseptic conditions and the suspension is filled into cleaned and sterilized 5 ml ampoules with stirring.

- 1-5 " -4ft-

Example 6

Two-compartment preparation with 9-deoxy-11-deoxy-9.1 i - ^ / Tmino / 2-'2-methoxyethoxy) ethylidene / oxyy- (9F) -erythromycin-lactobionate * N- (3,5-dibromo- 2-hydroxy-benzyl) -trans-4-hydroxy-cyclohexyl am. - »->' ^r hydrochloride (aqueous suspension)

composition

a) Dry ampoule

Antibiotic 3 575.0 mg

b) suspension solution ampoule

Active ingredient 500.0 mg

Polyethylene glycol stearate 5.0 mg sorbitol 1,250.0 mg

Methyl hydroxyethyl

cellulose 75.0 mg

Aqua pro injectione to 25.0 ml

analogous to example 5

However, they are filled in 30 ml or 25 ml injections vial.

Example 7

Injection solution containing oxytetracycline hydrochloride and N- (3,5-dibromo-2-hydroxy-benzyl) -trans ^ -hydroxy-cyclohexylamine

composition

Antibiotic χ HCl 5.0 g

Active ingredient 0.05-0.8 g

Magnesium oxide 0.45 g

pH correction 1.0 g

Antioxidants 0.2 g

Solketal 15, floor

1,2-propylene glycol 74.0 g

Aqua pro injectione to 100.0 ml

The antibiotic is dissolved in the appropriate amount of water and 1,2-propylene glycol in a suitable vessel and magnesium oxide is added. At the same time, a solution of solketal and active substance in the corresponding amount of 1,2-propylene glycol is prepared. The two active ingredient solutions are combined and a solution of the antioxidants in a little water is added. The desired pH value is set with pH correction. Production and filling are to be carried out under N ₂ gassing as well as aseptic conditions. Sterile filtration is necessary.

Example 8

Aqueous suspension containing chloramphenicol and N- (3,5-dibromo-2-hydroxy-benzyl) -trans-4-hydroxy-cyclohexylamine hydrochloride

composition

Antibiotic 20.0 g active substance 0.05-2.5 g suspension stabilizers 1.6 g Emulsifier 2.0 g

Citric acid 1.0 g

Antifoam 0.2 g

Thimerosal 0.005 g 1 η sodium hydroxide solution 3.25 g

Aqua pro injectione to 100.00 ml

Manufacturing

Thimerosal and citric acid are dissolved in about a third of the amount of water and placed in a suitable container. In This solution is in the order active substance, suspensionsi. Bilizers and anti-foaming agents added and dissolved or sus; euHert.

The emulsifier is dissolved in approx. 1/3 of the amount of water while warming and admitted. A suspension of chloramphenicol in water is added with stirring, the suspension becomes homogeneous the suitable pH value is set with 1 η NaOH, the remaining water is used to make up to 100 ml beforehand. All auxiliary and active ingredients or their solutions are sterilized before they are used. The production or filling must be aseptic Conditions take place.

Example 9

Injection solution containing tylosin and N- {2-amino-3,5-dibromo benzyP-N-methyl-cyclohexylamine hydrochloride

composition

Tylosin hydrochloride 50.0 mg

Active ingredient 0.5-6.0 mg

1,2-propylene glycol 0.5 ml

Benzyl alcohol 0.04 ml hydrochloric acid ad pH 4

Aqua pro injectione to 1.0 ml

Manufacturing

In 90 ml of an appropriate 1,2-propylene glycol-water mixture the active substance is dissolved with stirring and ultrasound treatment with nitrogen gas. Tylosin HCl is added and dissolved to give a clear solution. After adding the benzyl alcohol, 1 η HCl becomes the desired pH adjusted. It is made up to 100 ml with water.

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Production and filling must be carried out under aseptic conditions.

Example 10

Injection solution containing tylosin and N- (3-, 5-dibromo-2-hydroxy benzyP-trans ^ -hydroxy-cyclohexylamine hydrochloride

composition

Tylosin hydrochloride 50.0 mg

Active ingredient 0.5-6.0 mg

1,2-propylene glycol 0.5 ml

Benzyl alcohol 0.04 ml hydrochloric acid ad pH 4

Aqua pro injectione to 1.0 ml

Manufacturing
analogous to example 9

Example 11

Oil suspension containing erythromycin and N- (3,5-dibromo-2-hy droxy-benzy1) -trans - ^ - hydroxy-cyc lo hexylamine hydrochloride

composition

Erythromycin 50.0 mg Active substance 0.5-25.0 mg Dioctyl sulfosuccinate
sodium 2.0 mg Neutral oil ad 1.0 ml

Manufacturing

Dioctyl sulfosuccinate is used in the appropriate amount of neutral oil Sodium dissolved with heating and stirring. After cooling to ambient temperature, erythromycin is dissolved and the active substance is softened Particle size added. The resulting suspension we ^ κ't homogenized and under a suitable stirrer bottled aseptic conditions.

Example 12

Suspension containing erythromycin and N- (2-amino-3,5-dibromobenzyl ) -N-methyl-cyclohexylamine

Erythromycin 50.0 mg

Active ingredient 0.5-25.0 mg neutral oil 1.0 ml

analogous to example 11

Example 1 3

Injection solution containing trimethoprim, sulfadimidine, sulfathiazole and N- (2-amino-3,5-dibromobenzyl) -N-methyl-cyclohexylamine hydrochloride

composition

Trimethoprim 40.0 mg

Sulfadimidine 100.0 mg

Sulfathiazole 100.0 mg

Active ingredient 0.5-6.0 mg

Glycerin formal ad 1.0 ml

- ΖΌ -

Manufacturing

Active substance is under N ^ gassing in glycerol formal under Stirring dissolved. Trimethoprim, sulfadimidine and sulfathiazole are dissolved one after the other with stirring. Then with topped up with the remaining glycerine formal.

Production and filling must be carried out under aseptic conditions and protected from light.

Example 14

Injection solution containing trimethoprim, sulfadimidine, sulfathiazole and N- (3 _/ 5-dibromo-2-hydroxy-benzyl) -trans-4-hydroxy cyclohexylamine hydrochloride

Trimethoprim 40.0 mg

Sulfadimidine 100.0 mg

Sulfathiazole 100.0 mg

Active ingredient 0.5-15.0 mg

Glycerin formal ad 1.0 ml

analogous to example 13

Example 15

Injection solution containing spiramycin and N- (2-amino-3,5- dibromo-benzyP-N-methyl-cyclohexylamine hydrochloride

Active ingredient 0.5-6.0 mg

Spiramycin 50.0 mg

1,2-propylene glycol 0.5 ml

pro injectione -M- PH 1 - · ml ..3209.425 Hydrochloric acid ad 3 ad Aqua , 0 1 η ,8th

VJ krubstanz is under N ₂ gassing in 1,2-propylene glycol / Was. he mixture dissolved with stirring. Spiramycin is also dissolved. The desired pH value is set with 1 η HCl and topped up with water.

Production and filling are to be carried out under aseptic conditions.

Example 16

Injection solution containing spiramycin and N- (3,5-dibromo-2 hydroxy-benzyl) -trans-4-hydroxy-cyclohexylamine

composition

Active ingredient 0.5-15.0 mg Spiramycin 50.0 mg

Glucofurol ad 1.0 ml

In the solution of spiramycin produced under Nj gassing In glucofurol, the active substance is introduced in portions with further N. gassing and dissolved.

The filling takes place under aseptic conditions as well as N ₂ -gassing.

- T2 -

Example 17

Two-compartment preparation with 9-deoxy-11-deoxy-9,11- / imino £ 2- (2-methoxyethoxy) ethylidene / oxy / - (9F) -erythromycin lactobionate and N- (2-amino-3,5 -dibromo-benzyl) -trans-4-hydroxy-cyclohexylamine hydrochloride

composition

a) Dry ampoule

Antibiotic 715.0 mg

b) Solvent ampoule

Active ingredient 7 5.0 mg

Tartaric acid 37.5 mg

Glycerin Polyethylene Glycol Oxystearate 2 50.0 mg

Glucose 200.0 mg

Aqua pro injectione to 5.0 ml

Manufacturing
analogous to example 1

It goes without saying that all antibacterial substances that are difficult to absorb in veterinary medicine can be used or combinations, which were not expressly mentioned above, in the corresponding customary administration shape together with a benzylamine derivative.

Claims (6)

Claims Use of a benzylamine derivative of the general formula . (D in the R ₁ in the 2- or 4-position is a hydroxyl group or in the 2-position an amino group / R- is a hydrogen atom or an alkyl group of 1 to 3 Carbon atoms and R _{3 represent} a cyclohexyl group optionally substituted by a hydroxyl group, and its physiologically acceptable acid addition salts with inorganic or organic acids to improve the absorption of a non-optimally absorbable antibacterial substance or combination administered parenterally into the tissue. 2. Use of a benzylamine derivative of the general formula I according to claim 1, in which R _{1 is} as defined in claim 1, R_ and R- together with the intermediate nitrogen atom, the N-methyl-cyclohexylamino, N-ethyl-cyclohexyl -I- amino, trans-4-hydroxy-cyclohexylamino or cis-3-hydroxycyclohexylamino group represent, and its physiologically acceptable acid addition salts with inorganic or organic Acids to improve the absorption of a parenterally administered into the tissue not optimally absorbable antibacterial substance or combination. 3. Use of N- (3,5-dibromo-2-hydroxy-benzyl) -trans-4-hydroxy-cyclohexylamine and its physiologically compatible acid addition salts to improve absorption a non-optimally absorbable antibacterial substance or combination that is administered parenterally into the tissue. 4. Combination for parenteral administration into the tissue, containing a benzylamine derivative of the general formula I according to claim 1, in which R _{1 is} a hydroxyl group in the 2- or 4-position _f R is a hydrogen atom or an alkyl group of 1 to 3 Carbon atoms and R- represent a cyclohexyl group optionally substituted by a hydroxyl group, or its physiologically acceptable acid addition salts with inorganic or organic acids and one not optimally absorbable antibacterial substance or combination or N- (2-Amino-3,5-dibromobenzyl) -N-methyl-cyclohexylamine and its physiologically compatible acid addition salts and an oxytetracycline long-term preparation, oxytetracycline hydrochloride long-term preparation, Rolitetracycline, doxycycline, a sparingly soluble antibiotic of the β-lactam group, e.g. Procaine penicillin, benethamine penicillin, benzathine penicillin, a benzathine salt of oxacillin, cloxacillin, ampicillin and the cephalosporins, Erythromycin or one of its derivatives such as 9-deoxy-11-deoxy-9.11 - ^ Lnino - ^ - (2-methoxyethoxy) -äthyllder ^ - oxyy- (9F) -erythromycin, spiramycin, tylosin, oleandomycin or a sulfonamide such as sulfadiazine, sulfadoxine, sulfamethoxazole, »■ 'll.' ^ Dimethoxin, sulfadimidine or sulfathiazole or a Sulfonamide combination with an agonist such as trimethoprim, e.g. the sulfadimidine-sulfathiazole-trimethoprim combination, or N- (2-Amino-3,5-dibromobenzyl) -trans-4-hydroxy-cyclohexylamine as well as its physiologically acceptable acid addition salts and a tetracycline group antibiotic, e.g. B. Oxytetracycline, Oxytetracycline hydrochloride, RoI! Tetracycline or doxycycline, a sparingly soluble antibiotic of the β-lactam group, e.g. Procaine penicillin, benethamine penicillin, benzathine penicillin, a benzathine salt of oxacillin, cloxacillin, ampicillin and the cephalosporins, Erythromycin or one of its derivatives such as 9-deoxy-11-deoxy-9,11- / imino- / 2- (2-methoxyethoxy) ethylidene? oxy _ / - (9F) -erythromycin, spiramycin, tylosin, oleandomycin, Chloramphenicol or a sulfonamide, e.g. sulfadiazine, sulfadoxine, Sulfamethoxazole, sulfadimethoxin, sulfadimidine or Sulfathiazole, or a sulfonamide combination with an agonist such as trimethoprim, e.g. B. the sulfadimidine-sulfathiazole-trimethoprim combination, and, if applicable, their corresponding forms of deposit. 5. Combination for parenteral administration into the tissue, containing a benzylamine derivative of the general formula I according to claim 1, in which R _{1 is} as defined in claim 4, R- and R, together with the intermediate nitrogen atom, the N-ethyl-cyclohexylamino-, trans Represent -4-hydroxy-cyclohexylamino or cis-3-hydroxy-cyclohexylamino groups, or their physiologically acceptable acid addition salts with inorganic or organic acids and a non-optimally absorbable antibacterial substance or combination. 6. Combination for parenteral administration into the tissue containing a non-optimally absorbable antibacterial substance or combination and N- (3,5-dibromo-2-hydroxybenzyl) -trans-4-hydroxy-cyclohexylamine or its physiologically compatible acid addition salts with inorganic or organic acids.